In the United States, breast cancer is the most common cancer diagnosed in women and is the second leading cause of death in women after lung cancer. It is estimated that 212,920 new cases of invasive breast cancer will be detected among women in the United States in the 2006 and 40,970 women will die from this disease in the same year. Approximately 60% of premenopausal and 75% of postmenopausal breast cancer patients have estrogen-dependent carcinoma. Hormone-dependent breast tumors require estrogens for their growth and are characterized by high expression of estrogen receptors (ERs). As a result, efforts to block estrogen action by interfering with the binding to its receptor or by decreasing estrogen production are used as strategies to treat hormone-dependent breast cancer. The first approach involves antiestrogen molecules that can compete with estrogen for binding to the ERs. The second method utilizes aromatase inhibitors (AIs) that inhibit the enzyme catalyzing the final rate-limiting step of the estrogen biosynthesis.
Significant research has focused on developing antiestrogens that can selectively inhibit the estrogen effects in breast tissue without antagonizing the physiological roles of estrogens in other tissues. Agents that exhibit such tissue-specific antiestrogenic/estrogenic activities have been termed selective estrogen receptor modulators (SERMs). Tamoxifen is the most widely used SERM in hormone-dependent breast cancer therapy and has made a substantial contribution to the reduced mortality rate in many developed countries since 1990. Although tamoxifen is still considered the “gold standard” for endocrine therapy in hormone-dependent breast cancer, its use is associated with tumor resistance and increased risk of endometrial cancer. Aromatase inhibitors, such as anastrozole, letrozole, and exemestane, significantly decrease plasma estrogen levels, are emerging as alternatives to tamoxifen due to their clinical efficacy, and have favorable safety profiles for the treatment of hormone-dependent breast cancer in postmenopausal women. However, since the AIs inhibit aromatase enzyme in a global fashion, a major long term side effect of the AIs is the reduction of the bone density which can lead to osteoporosis.
To reduce the risk of the long term side effects, a new pharmacological approach in the treatment of estrogen dependent postmenopausal breast cancer is the use of tissue-specific inhibitors of aromatase. This concept is based on the tissue-specific regulation of aromatase expression. Ten different promoter regions have been identified upstream of the coding region of the aromatase gene (CYP19). The employment of alternative promoters results in tissue specific regulation of the CYP19 expression. Each promoter is regulated by distinct hormones and second messenger pathways. In postmenopausal women, estrogens are produced by adipose tissue, including breast tissue and skin. In these tissues aromatase expression is directed by promoter 1.4 that is regulated by the synergistic actions of glucocorticoids and class I cytokines such interleukin (IL)-6, IL-11 and tumor necrosis factor alpha (TNFα). In breast adenocarcinoma, aromatase expression and activity increase significantly compare to normal breast tissue. Breast tumors produce factors that stimulate aromatase expression locally. This stimulation is associated with switching of aromatase gene promoter from promoter I.4 to c-AMP dependent promoter I.3 and promoter II in breast cancer and surrounding adipose stromal cells. Current evidences suggest that tumor-derived factors, including the cyclooxygenase (COX) product prostaglandin E2 (PGE2), can mediate the induction of aromatase expression via promoter II by stimulating adenylate cyclase in adipose stromal cells. This biochemical mechanism may explain epidemiological observations of the beneficial effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on breast cancer.
There exists a need for new compounds for treating breast cancers and other cancers as well as new synthetic approaches to making such compounds.